Longevity steps on the cGAS.

The first line of defense that cells have against foreign pathogens is an innate immune response. Cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) plays a crucial role in this response by detecting pathogen- derived DNA or RNA in the cytosol of the host cell and initiating a signaling cascade that causes the transcription of genes encoding type I interferons (1). Increased inflammation is a hallmark of aging (2), and dysregulation of cGAS signaling during aging can drive debilitating inflammatory processes (3, 4). Therefore, cGAS was proposed as a therapeutic target. However, although present in the cytosol, cGAS is predominantly bound to chromatin, and its role in the nucleus is unclear (5). On page 150 of this issue, Chen et al. (6) report that cGAS from the naked mole-rat has a distinct set of four mutations on its N terminus that promote DNA repair—a mechanism crucial to the organism's extreme longevity. [ABSTRACT FROM AUTHOR]